Congenital obstructive nephropathy is a major cause of chronic renal failure and is the etiology in approximately 10-15% of end stage renal disease (ESRD) in children. It has been demonstrated that obstruction of the renal tubular and/or ureteric system at an early stage of development is an important cause of cystic dysplasia, and ureteric obstruction at a later stage leads to congenital hydronephrosis. It has also been show that an alteration in metanephric induction and differentiation is an important pathophysiological event in cystic dysplasia, and changes in the expression of paracrine growth factors, such as the insulin-like growth factor (IGF) system, play an important role. In order to further our understanding of the prenatal pathogenesis as well as to develop therapeutic strategies for improving the outcome of obstructive nephropathy and renal dysplasia, relevant animal models that closely parallel human developmental processes are essential. The studies outlined in this project focus on the development of an in vivo fetal monkey model of renal obstructive disease and dysplasia with the goal of studying the histopathologic progression of obstructive nephropathy (Specific Aim 1), and assessing the pattern of expression of IGF genes and apoptotic markers (Specific Aim 2). The long-term objectives of these studies include: to further our understanding of the pathophysiology of obstructive renal disease in the fetal monkey as a model for the human compromise, and to investigate novel and optimal in utero approaches for reversing and/or preventing renal dysplastic changes. The fetal monkey model incorporates a nonsurgical, ultrasound-guided method for inducing unilateral ureteral obstruction during the early second trimester, with sonographic monitoring of in utero renal anatomical and hemodynamic changes (B-mode imaging, pulsed and color Doppler), and assessments of effects on amniotic fluid volume and urinary and amniotic fluid biochemistry and growth factors (IGF-I, IGF-II, IGFBP-I, IGFBP-3). Both non-obstructed and obstructed fetal monkey kidneys will be studied at various time points during the second and third trimesters and at term in order to evaluate the histopathologic progression of obstructive nephropathy, and to assess the pattern of expression of IGF-I and -II, and IGFBP-I, -2, and -3. Apoptosis will also be studied as a marker of renal damage using immunohistochemical and molecular markers, and the expression of apoptotic-related genes.